Date: Fri, 25 Feb 1994 10:54:11 -0500 (EST)
From: "ANNE WILSON, CDC NAC"
Subject: NIH Executive Summary re: Perinatal AZT
E X E C U T I V E S U M M A R Y
******************************************
NATIONAL INSTITUTES OF HEALTH
National Institute of Allergy and Infectious Diseases
February 20, 1994
EXECUTIVE SUMMARY: ABSTRACT ACTG 076
A Phase III Randomized, Placebo-Controlled Trial to Evaluate the
Efficacy, Safety and Tolerance of Zidovudine (ZDV) for the Prevention of
Maternal-Fetal Transmission
BACKGROUND
Currently, there are approximately 10-20,000 HIV-infected children and
approximately 7,000 infants are born annually to HIV-infected women in the
United States. It is estimated that by the year 2000, 10 million children
globally will have been infected.
The vast majority of HIV-infected infants and children acquire the virus
by maternal-infant transmission; either in utero, during labor and
delivery, or postpartum via breastfeeding. In the developed world,
antepartum and intrapartum routes account for nearly all of the cases.
The risk of matern al-infant HIV transmission in pregnant women has been
associated with advanced disease stage, low CD4+ lymphocyte count, and
high viral burden.
Zidovudine (ZDV) has been demonstrated to be an effective treatment to
decrease viral burden and delay disease progression for HIV-infected
adults and children. An uncontrolled survey of some pregnant women
treated with ZDV for their own medical care revealed no significant
untoward effect.
The risk of maternal-infant transmission of HIV theoretically could be
reduced by ZDV treatment of pregnant women. To test this hypothesis,
in April, 199 1, a Phase III randomized, double-blind, placebo-
controlled clinical trial (AC TG 076) was initiated to evaluate whether
ZDV therapy could reduce the risk of maternal-fetal transmission in HIV-
infected pregnant women. An additional study objective was to evaluate
the safety of the ZDV regimen for mothers a nd infants.
METHODS
Eligible patients were HIV-infected pregnant women (between 14 and 34
weeks gestation) who had no antiretroviral treatment during the current
pregnancy, had baseline CD4+ lymphocyte counts greater than 200 cells/
mm3, and had no clinical indications for maternal antepartum ZDV
therapy. The target sampl e size was 748 women (636 fully assessable
mother-infant pairs). This was chosen so as to provide 80 percent power
to detect a reduction in the probability of transmission to 20 percent
for the ZDV group compared with 3 0 percent for the placebo group, using
a two-sided, alpha=0.05 test. Women w ere stratified according to
gestational age (14-26 weeks; >26 weeks) and randomized to receive
either ZDV or placebo.
The ZDV regimen consisted of antepartum ZDV (100 mg p.o. five times
daily) plus intrapartum ZDV (IV loading dose, 2 mg/kg, followed by
continuous infusion, 1 mg/kg/hr, until delivery) plus newborn ZDV
(syrup, 2 mg/kg q. 6 hr for six weeks beginning 8-12 hours after birth).
Pregnant women were seen frequently during pregnancy, through delivery,
and for six months postpartu m, and were carefully assessed for evidence
of drug toxicity, HIV disease progression, and fetal well-being.
Infants were carefully monitored throug h 78 weeks of age for evidence
of HIV infection and to assess safety. HIV infection status was
determined by viral culture from the infants at birth, 12 weeks, and 78
weeks of life, and samples were obtained for HIV serology at 72 and 78
weeks. A protocol modification added an additional culture at 24
weeks. Infants were defined as HIV infected for the primary analysis
based on one positive viral culture obtained from peripheral blood.
On February 17, 1994, the ACTG Data and Safety Monitoring Board (DSMB)
reviewed the interim analysis based on information in the database as of
December 20, 1993, and concluded that there was significant evidence of
treatment efficacy. On February 18, 1994, the Pediatric AIDS Clinical
Trials Group Executive Committee approved the DSMB recommendations to:
(1) discontinue new patient enrollment; (2) offer open-label ZDV as
per protocol regimen to all individuals on the study; and (3) continue
long term follow-up of all infants participating in ACTG 076 to monitor
for possible development of unknown late effects of the study treatment.
RESULTS
Thirty-five NIAID sponsored sites, 15 NICHD sponsored sites, and nine
centers in France enrolled patients in ACTG 076. Four hundred seventy-
seven women were enrolled as of the December 20, 1993 data cut-off. The
median age was 25 years (range, 15-43), the median CD4+ lymphocyte count
was 550 cells/mm3 (range, 200-1818), and 41 percent of women had CD4+
lymphocyte counts betwe en 200 and 500 cells/mm3. The median
gestational age at entry was 26 weeks. Maternal demographics revealed a
predominantly minority population: only 1 9 percent were white/non-
Hispanic.
Four hundred twenty-one babies have been born; 409 singletons and 6 sets
of twins. The median gestational age at delivery was 39 weeks (range,
27-43 weeks). Three sets of twins and 23 singletons were premature (<36
weeks gestation). The median 1-minute Apgar score was 8 (range, 0-10),
the median 5-minute Apgar was 9 (range, 5-10), and the median birth
weight was 3160 gr ams (range, 1040-5267 grams). Seven infants (1.7
percent) weighed <1500 grams at birth, 14 (3.4 percent) weighed between
1500 and 2000 grams, and 44 (10.7 percent) weighed between 2000 and 2500
grams.
Three hundred sixty-four births were included in this interim efficacy
analysis, 180 in the ZDV group and 184 in the placebo group. Two
hundred thirty-three infants had information about HIV infection status
as of 24 weeks of life, and 75 of these had confirmation at 18 months.
Thirteen babies in the ZDV group and 40 in the placebo group were
defined as HIV-infected. Th e estimated percentages infected based on
Kaplan-Meier analysis were 8.3 perc ent (s.e.: 2.25 percent) in the ZDV
group and 25.5 percent (s.e.: 3.60 percent) in the placebo group. The
estimated absolute difference in percentage infected between the two
groups was 17.2 percent, with 95 percent confidence interval 8.9 to 25.5
percent. This corresponded to a 67.5 relative reduction in transmission
risk. This risk reduction is highly statistically significant (z=4.03;
two-sided p=0.000056).
Reported maternal and infant side effects were balanced between the two
randomized groups, with one exception that hemoglobin levels were lower
for infants in the ZDV group. The mean decrease in hemoglobin was less
than 1 g/dl, did not require transfusion, and resolved after completion
of ZDV therapy.
CONCLUSIONS
A treatment regimen consisting of ZDV given to the mother both
antepartum and intrapartum, as well as to the newborn during the first
six weeks of life, significantly reduced the risk of maternal-infant
transmission of HIV for women with baseline CD4+ lymphocyte counts >200
cells/mm3. Further follow-up of mothers and infants is being conducted
to determine if there are any lat e adverse effects of this treatment
regimen. Any decision to institute thera py regimens for the prevention
of maternal-fetal transmission must be made aft er careful consideration
of the potential unknown long term risks.
Prepared by:
Richard D. Gelber, Ph.D.
Pavel Kiselev, Ph.D.
Edward Connor, M.D.
Rhoda Sperling, M.D.
John Moye, M.D.
Mary Culnane, M.S., C.R.N.P.
Bethann Cunningham, M.S.